This career (K08) award applies specified funding, 75 percent research time and a 5-year plan to develop the candidate's experience and expertise, in the understudied area of psychopharmacologic research in persons with autism and mental retardation (MR). A primary goal is for the candidate to learn from Dr. Schroeder how behavioral observation and Applied Behavior Analysis can be used in research in this population. By performing a double-blind drug study, with Dr. Schroeder's weekly supervision, regular internal and expert-consultation and attending research didactic courses, the candidate will develop into an independent psychopharmacology researcher with expertise in behavioral observation and intervention techniques. The proposed study aims to test the hypothesis that aggressive autistic adolescents will show a significantly greater response to valproate maintained at blood levels of 75-100 mcg/ml than to placebo (PRO), in a double-blind case-controlled design. The study will also critically assess the safety of valproate in autistic adolescents. The study will be performed over 5 years, on 30 outpatient autistic adolescents aged 10 to 19 years, referred to the University outpatient MR/Autism Clinic for aggression. Study candidates will undergo DSM-IV evaluation, the ADI-R and ADOS, and baseline blood tests. Exclusion criteria will include degenerative CNS disorders, unstable medical illness, seizures in the past 6 months, a history of valproate sensitivity or previous liver disease, a history of ovarian cysts in girls, a low platelet count or raised liver transaminases. No other psychoactive maintenance medication will be allowed. Any level of MR (IQ<70) will be permissible. After baseline screening, and a 1-week placebo lead-in, subjects will be randomized to PBO or valproate for 8 weeks. Dosage adjustment according to blood levels drawn at the end of weeks 2 and 4 will be arranged with parents by a child psychiatrist without breaking the blind. The Aberrant Behavior Checklist-Community (ABC-C) irritability subscale will be the primary measure; the Overt Aggression Scale (OAS), ABC-C hyperactivity subscale, Clinical Global Impressions (CGI) problem severity, Self-Injurious Behavior Questionnaire (SIB-Q), and a valproate side effects checklist will be secondary measures. Primary measure scores obtained will be analyzed using a multivariate analysis of variance comparing drug placebo groups pre- and post-treatment. The secondary measures will be analyzed using a multivariate analysis of variance. Study results will be prepared and submitted as manuscripts for publications and presentations. Achievement of goals of the grant will be monitored by Dr. Schroeder weekly, quarterly and annually.